B Cell Maturation Antigen CAR-T Research Articles

PD-1 downregulation enhances CAR-T cell antitumor efficiency by preserving a cell memory phenotype and reducing exhaustion

BackgroundDespite the encouraging outcome of chimeric antigen receptor T cell (CAR-T) targeting B cell maturation antigen (BCMA) in managing relapsed or refractory multiple myeloma (RRMM) patients, the therapeutic side effects...

CD70 CAR NK Cells in the Treatment of Multiple Myeloma

Despite the high response rates of chimeric antigen receptor (CAR) - T cells targeting the B-cell maturation antigen (BCMA) for multiple myeloma (MM), patients eventually still relapse. At this time there is no clear subsequent therapy. Furthermore, CAR T-cell therapy is associated with significant toxicities such as cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome. CD70 is a normally transiently expressed on activated T-cells, B-cells, or dendritic cells, but have been found to be upregulated on many hematologic and solid cancer cells such as acute myeloid leukemia, triple negative breast cancer, and renal cell carcinoma. However, CD70 as a potential target for treatment of multiple myeloma, including patients who have progressed on BCMA targeted therapies, has not been fully investigated. We assessed bone marrow aspirates from MM patients by flow cytometry and demonstrated that CD70 was expressed on the majority of myeloma cells, and on average, relapsed myeloma patients had higher expression of CD70. In addition, using immunohistological staining, we found that CD70 was expressed on 10 of 10 patients who had progressed on BCMA targeted therapies (seven who had progressed on belantamab mafodotin, an antibody drug conjugate, three who had progressed on idecabtagene vicleucel, a BCMA CAR-T), suggesting that CD70 could be a viable target in patients who have failed BCMA targeted therapy. As natural killer (NK) cells are a promising off-the-shelf treatment with minimal toxicity as compared to CAR-T cells, we generated CD70-targeting CAR NK cells for the treatment of MM. We found in the chromium cytotoxicity assay that CD70 CAR NK cells had higher killing as compared to non-transduced (NT) NK cells at multiple effector-to-target ratios against MM1s, a myeloma cell line confirmed to express CD70. There was no difference in killing when co-cultured with H929, a myeloma cell line lacking CD70 expression, demonstrating the specificity of the CD70 CAR NK cell. The enhanced killing was also confirmed in an incucyte assay in which the CD70 CAR NK cells cleared tumor faster than NT NK, even in MM1s in which BCMA was knocked out using CRISPR (simulating BCMA antigen loss). When tested in a myeloma mouse model, the CD70 CAR NK exhibited greater tumor control as shown in Figure 1, when compared to NT NK, which lead to increased survival of the mice. Similar results were seen in a mouse model using BCMA KO myeloma cells. In summary, we were able to demonstrate that CD70 can be a feasible target for the treatment of multiple myeloma, including in patients who have failed BCMA targeted therapy. Based on these results, we have initiated a Phase I/II clinical trial (NCT05092451) that is currently recruiting.

Safety and Efficacy of GPRC5D CAR T Cell Therapy in Relapsed/Refractory Multiple Myeloma Patients

B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T-cell therapies have shown breakthrough therapeutic effects in treating relapsed/refractory (R/R) multiple myeloma patients. However, relapses, including some that are BCMA negative, remain a challenge. Here we have developed a second-generation GPRC5D CAR-T, composed of a GPRC5D-binding scFv (derived from a humanized rabbit monoclonal antibody), a 4-1BB costimulatory domain, and a CD3ζ signaling domain. Following pre-clinical studies, we initiated a phase 1 dose-escalation clinical trial. Lymphodepletion with fludarabine and cyclophosphamide was performed before administering 3E6, 6E6, or 1E7/kg anti-GPRC5D CAR T cells. To date, we have enrolled a total of 7 R/R MM patients, including 3 patients with prior BCMA CAR-T treatment. All patients received autologous CAR T-cell infusions and were clinically evaluated between February 7th, 2023, and June 26th, 2023. No dose-limiting toxicities (DLT) were observed, even at the highest dose of 1E7/kg. Grade 3 or higher adverse events (AEs) were mainly hematological toxicities, such as neutropenia (6 [85.7%]), anemia (3 [43%]), and thrombocytopenia (3 [43%]). Cytokine release syndrome occurred in 6 (85.7%) of 7 patients, with all cases classified as grade 1 or 2. Notably, no neuro-toxicities were observed in any of the seven patients. The overall response rate was 85.7% (6/7 patients), comprising 3 complete responses or better, 3 partial responses, and one no-response (NR). The NR patient had previously shown no response to BCMA CAR-T therapy, with FACS analysis confirming the absence of both BCMA and GPRC5D on their tumor cells. Interestingly, the other two patients previously treated with BCMA CAR T-cell therapy, one reached complete response (CR), and the other reached partial response (PR). Remarkably, one patient diagnosed as COVID-19 positive two days before CAR-T infusion still received the CAR-T cell product, which led to a dramatic in vivo expansion of CAR-T cells, resulting in CR within one month after cell infusion. In conclusion, GPRC5D CAR T-cell therapy demonstrated promising clinical efficacy and tolerable safety in patients with R/R MM. For those who relapsed after anti-BCMA CAR T-cell therapy, GPRC5D CAR T-cell therapy offered an effective option (NCT05739188).“

Ablation of Cullin-5 in Primary Human T Cells Improves Tumor Killing and Persistence in BCMA-Targeting CAR-T Cells in a Multiple Myeloma Model

While adoptive T cell therapies have led to remarkable clinical responses in certain subsets of B cell leukemia and lymphoma, many challenges remain that are limiting the efficacy in other hematological malignancies. Compromised T cell function and exhaustion due to chronic antigen exposure can impair the persistence of chimeric antigen receptor (CAR)-T and T-cell-receptor (TCR)-T cells. Gene editing strategies have the potential to circumvent some of these challenges and enhance T cell function. To identify key genes that are involved in regulating T cell dysfunction, we performed a genome-wide CRISPR loss-of-function screen in primary human T cells in conditions that mimic chronic antigen exposure. Primary T cells from two donors were transduced with lentivirus containing a NY-ESO-1 TCR as well as a genome-wide sgRNA library and subsequently CRISPR edited using Cas9-RNP electroporation. These antigen specific TCR-T cells were then co-cultured with the NY-ESO-1+ melanoma cell line A375 at an effector-to-target (E:T) ratio of 1:1 for 48 hours and challenged under the pressure of chronic tumor stimulation for 9 rounds in total. The resulting next-generation sequencing data was then analyzed utilizing the MAGeCK pipeline to identify top scoring hits for validation regarding their role in T cell fitness and persistence. Among the hits with the highest positive fold changes, we found seven genes which are part of the Cullin-RING ligase 5 multi-protein complex (Fig. 1). These hits were then validated in a CAR-T cell context. We first edited primary human T cells by knocking out CUL5 as well as the endogenous TCR. The template for the B Cell Maturation Antigen (BCMA)-specific CAR bb2121 was then delivered to the TRAC locus via CRISPR/Cas9-RNP and adeno-associated virus (AAV). Here, we tested a panel with four CAR modifications, including two different co-stimulatory domains (CD28ζ, 4-1BB), a CAR with mutated immunoreceptor tyrosine-based activation motifs (ITAM) (1XX CAR), and a CAR containing an alternative BCMA-targeting single-chain variable fragment. This panel of CUL5 ablated CAR-T cells were then repeatedly co-cultured with BCMA-expressing tumor cells. After 6 rounds of tumor exposures, CUL5 ablated T cells showed a striking tumor killing advantage compared to control edited cells in a functional tumor killing assay (Fig. 2). Notably, we also observed vastly increased production of the cytotoxic cytokines INF-γand TNF-α in CUL5 ablated cells. Furthermore, the distinct tumor killing advantage of CUL5 KO cells in vitro was reproduced in the context of a CD19-specific CAR, which will be relevant in other clinical settings. Finally, we evaluated the striking tumor killing capacity of CUL5 ablated BCMA-specific CAR-T cells in vivo. For this, NOD.Cg- PrkdcscidIl2rgtm1Wjl/SzJ mice engrafted with luciferase-expressing BCMA+ multiple myeloma cell line OPM2 were treated with this panel of CUL5 ablated and control CAR-T cells and tumor burden was measured via Bioluminescent Imaging (BLI) over time. Mice treated with CUL5 KO BCMA-specific CAR-T cells showed lower median radiance measured by BLI, except for the 1XX CAR condition where both cohorts completely cleared the disease. In addition to the complete tumor clearance in both the control and CUL5 edited cohorts, we observed that the BLI levels in the 1XX CAR treated animals remained stable even after the mice were subjected to five tumor rechallenges. After 90 days, the mice were sacrificed and CAR+ human T cells were isolated from the bone marrow and spleens and phenotypically assessed. Analysis of these samples revealed a significantly higher frequency of CAR+ cells in the mouse bone marrow in the CUL5 KO group compared to control, while there were equivalent numbers in the spleens, suggesting an antigen-specific expansion advantage for the CUL5 KO CAR-T cells. We then co-cultured the isolated BCMA CAR-T cells from the spleens of these mice with OMP2 tumor cells in different E:T ratios and assessed tumor killing. We found a significant advantage in tumor killing of CUL5 ablated T cells compared to control cells in this ex vivo setting, suggesting an improved functional persistence. In summary, our findings identify the CUL5 complex as a novel potential therapeutic target to improve T cell persistence and counteract T cell exhaustion in order to improve the efficacy of adaptive cell immunotherapies for the treatment of BCMA+ hematological malignancies.

BCMA CAR-T-Cell Therapy in Combination with Long-Term Pomalidomide Is a Safe and Effective Treatment for Relapsed/Refractory Multiple Myeloma

Background: B-cell maturation antigen (BCMA)-targeted chimeric antigen receptor T-cell (CAR-T-cell) therapy has exhibited remarkable efficacy in refractory or relapsed multiple myeloma (R/R MM), but recurrence and rapid progression of disease are still observed in some cases within a short time after treatment. Long-term pomalidomide therapy, which potentiates T-cell functionality and has direct antimyeloma effects, might enhance the efficacy of BCMA CAR-T-cell therapy. Here, we present the efficacy of this combination regimen for R/R MM. Methods: We performed a single-center prospective clinical study that was registered with the Chinese Clinical Trial Registration Center (ChiCTR2000036350). Patients with relpased or refractory multiple myeloma receiving BCMA CAR-T cell infusion were randomized to receive long-term pomalidomide treatment (4 mg/day) one month after infusion. The primary endpoint is overall survival (OS) in R/R MM with long-term pomalidomide administration compared to those without pomalidomide therapy after CAR T-cell infusion. The secondary endpoints include time to progression (TTP) and therapeutic response. Also, the copy numbers of CAR were assessed after infusion. Results: A total of 14 R/R MM patients who received BCMA CAT T-cell therapy, were included in this study. The median age of the enrolled R/R MM patients was 59.5 years (44-71). Five patients had high-risk cytogenetic abnormalities (IGH rearrangement, 1q21 amplification, and P53 deletion) at the time of initial diagnosis. In addition, high-risk genetic alterations were newly detected in patient 2 during first-line therapy. All patients had previously received 3 to 6 lines of treatment with proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), or anti-CD38 monoclonal antibodies. As shown in Figure 1, all patients had demonstrated progressive disease prior to CAR T-cell infusion. The objective response rate (ORR) of BCMA-CART was 100%. Three months following CAR-T-cell infusion, of the 6 patients receiving pomalidomide, all patients (6/6) achieved VGPR (very good partial response) or CR (complete response）, while only 5 patients (5/8) who did not receive pomalidomide treatment achieved VGPR or better. At a median follow-up of 19.7 months, for the 8 patients who did not receive pomalidomide administration, the median TTP (time to progression) was 4.5 (1-14) months, while the TTP was not reached in patients who received long-term pomalidomide treatment. Moreover, the dynamic abundance of circulating BCMA CAR-T cells was monitored as shown in Figure 2. In patients who received pomalidomide treatment after CAR-T-cell therapy, the CAR copy numbers of circulating CAR-T cells peaked 8 to 10 days after CAR-T-cell infusion, with a peak copy number of up to 10 6. In addition, BCMA CAR-T cells persisted (>1*10 3 copies/µg DNA) for 3 months in vivo. Without pomalidomide administration, BCMA CAR-T cells persisted for up to 2.5 months in the peripheral circulation (results not shown). Conclusion: Our results confirm the efficacy of the long-term oral pomalidomide administration (4 mg/day) after BCMA CAR T-cell infusion in patients with R/R MM. Notably, this combination regieme reduced the recurrence rate and prolonged progression-free survival for R/R MM patients, providing a promising option for treating R/R MM. In addition, oral administration of pomalidomide did not significantly prolong the persistence of BCMA CAR T-cells in vivo. However, data from studies with larger sample sizes are required to draw valid conclusions.

B-Cell Maturation Antigen (BCMA) Expression and Clinical Features of Plasmablastic Lymphoma (PBL)

Introduction: Plasmablastic lymphoma (PBL) is a rare and aggressive subtype of large B-cell lymphoma with plasmacytic differentiation. Although limited-stage (LS) PBL has a favorable outcome, extensive-stage (ES) PBL has a poor prognosis, with a median survival of 12-18 months. Patients with relapsed/refractory (r/r) PBL have limited treatment options and most die from the disease. B cell maturation antigen (BCMA) - directed cellular and immunotherapies are highly effective in MM. The data on BCMA expression in PBL is limited. Literature review identified one report including 7 PBL cases all of which expressed BCMA. We studied all patients with a diagnosis of PBL who presented to Moffitt Cancer Center in Florida, USA from Jan. 2006 to Apr. 2023, and retrospectively performed BCMA immunohistochemistry (IHC) staining on the available archived FFPE biopsy samples. Methods: Progression-free survival (PFS) was calculated as time from disease progression or last follow up to treatment start date. Overall survival (OS) was calculated as time from death or last follow up to date of PBL diagnosis. Association of BCMA expression with PFS or OS was evaluated using logrank test, with continuous variables converted to categorical by classifying as above or below median. All analyses were done using SAS 9.2. Results: A total of 32 PBL patients were identified. The median age was 59 years (range 31-83 years); 21 (65.6%) had stage III/IV (ES); 9 patients (28.1%) were HIV positive; and 57.1% of evaluated cases were EBV positive by EBER. Treatment data was available for 30 patients. The most common frontline therapies were EPOCH and CHOP with or without rituximab; four patients received bortezomib combined with EPOCH; 7 patients (23.3%) received autoSCT in 1 st remission (Table 1). Median follow-up was 77.6 months calculated using the reverse Kaplan-Meier method. Consistent with previous reports, patients with ES PBL had worse outcome than those with LS PBL, with 3-year OS rates of 24% and 100%, respectively, p=0.01 (Table 1). Among the 20 patients with ES PBL and known treatment responses, 11 did not achieve CR after frontline therapy. Ten of these 11 patients died due to disease progression, 9 within 2 years and 1 within 3 years. Two patients received CD19 CAR-T after multiple lines of therapy. Both died within 30 days, one from disease progression and the other from multiple treatment complications. Out of the 18 cases with tissue available for IHC study, 17 (94.4%) had positive BCMA expression (Figure 1). The median percentage of BCMA+ cells was 75% (Table 1). Eleven (61.1%) cases had intermediate to strong BCMA staining. Neither BCMA+ cell percentage nor BCMA expression level was associated with disease stage, response rate, PFS, or OS (p>0.10 for all tests). Discussion: In our study the majority of our PBL cases tested positive for BCMA, and the percentage of BCMA+ cells seemed comparable to MM cases.To our knowledge, this is the largest and the first report that systemically evaluated BCMA expression in PBL. Our results provide evidence to explore BCMA as a potential target in PBL. Currently two anti-BCMA CAR-T products and an anti-BCMA/CD3 bispecific T-cell engager have been approved for r/r MM. A BCMA-targeting antibody-drug conjugate (ADC) Belantamab mafodotin-blmf was initially granted accelerated approval by FDA for r/r MM but was later voluntarily withdrawn from the market. Given the expression of BCMA in PBL and the lack of effective treatment of r/r PBL, these patients could be considered in trials evaluating the BCMA-targeting therapies. In fact, in a case report recently published, one patient with refractory PBL achieved CR after one infusion of BCMA CAR-T and remained in CR after 14 months. Ten of our 11 ES patients who did not achieve CR after frontline chemotherapy died from the disease, emphasizing the importance of clinical trials for this condition. We did not find an association of BCMA expression with clinical outcomes as oppose of MM, in which higher BCMA expression was associated with shorter PFS and OS. The lack of association in our study may be due to the small sample size, or, it may reflect a difference in biological role of BCMA in PBL from MM. Our results will need to be corroborated with other series to confirm our findings. Translational studies need to evaluate the dynamics of BCMA protein expression on PBL cell membrane and the activity of BCMA-targeting agents in vitro and in animal models of PBL.

Lymphodepletion Enables Successful BCMA CAR-T Cell Engraftment and Tumour Control in the Syngeneic Vk*MYC Model of Aggressive Myeloma

DISCUSSION AND CONCLUSION Chimeric antigen receptor (CAR)-T cells directed against B-cell maturation antigen (BCMA), have yielded impressive results in clinical trials for multiply relapsed/refractory multiple myeloma (MM). However, progression-free survival is short, demonstrating a need for improvements. While numerous advances have been made to improve this treatment modality, these have not always translated to superior clinical outcomes. A major limitation is that novel therapeutics are often not tested in a relevant in vivo model. These novel strategies have been largely tested only in immunodeficient models of MM. To better recapitulate the host-tumour-effector cell interactions, particularly in the TME, we sought to develop a system to study CAR-T cell activity in the Vk*MYC model of MM. Here, we report on the first known successful model of CAR-T cell activity in an immunocompetent model of MM. We sought to identify a BCMA CAR construct that is capable of binding to both human and mouse BCMA. A novel nanobody recognizing BCMA was developed by immunizing llamas with human BCMA and the resulting single-domain antibodies (sdAbs) were subsequently isolated and cloned. These sdAbs were then screened for binding to mouse BCMA. A binder capable of recognizing both human and mouse BCMA was identified and cloned into our murine CAR construct, with CD28 and CD3z signaling domains, herein referred to as sdBCMA2.CD28.CD3z. Murine CAR-T cells were then generated by transducing activated healthy murine splenocytes with a retroviral vector carrying the sdBCMA2.CD28.CD3z construct. These CAR-T cells were then characterized in vitro using standard cytotoxicity, proliferation, and cytokine release assays. To assess activity in an immunocompetent model, female C57BL/6J mice were injected intravenously with Vk12598 Vk*MYC cells. CAR-T cells were later administered intravenously. Mice were bled weekly to quantify M-protein disease burden by serum protein electrophoresis and for phenotypic characterization of circulating cells. When co-cultured with BCMA+ human MM cell lines and with Vk*MYC cell lines, murine sdBCMA2.CD28.CD3z CAR-T cells effectively lysed target cells, proliferated, and released inflammatory cytokines. To assess the in vivo activity of these CAR-T cells, we injected intravenously female C57BL/6J mice with Vk12598 cells, and then administered sdBCMA2.CD28.CD3z CAR-T cells intravenously. While there was some evidence of survival improvement, the median overall survival (mOS) of 35 days compared to 28 days, for CAR-T vs. Mock T-cells, respectively, the difference was non-significant, and the survival benefit was not durable. To address this, we incorporated lymphodepletion by total body irradiation (TBI) followed by CAR-T cell administration the next day. By incorporating lymphodepletion prior to CAR-T cell administration we were able to significantly reduce M-protein surrogates of disease burden, as well as achieve durable remissions in the TBI + CAR-T arm with an mOS not yet reached after experimental day 91, compared to an mOS of 42 days in the TBI + Mock T-cell arm. The addition of TBI also significantly improved the engraftment of CAR-T cells, as assessed by flow cytometry. The TBI + CAR-T arm also had significantly increased IL-6, IL-1b, IL-2, and TNF-a in the serum, compared to the TBI + Mock arm, at 7 days post administration of CAR-T cells. The durable remission achieved using the combination of our novel sdBCMA2.CD28.CD3z CAR-T cells with lymphodepletion is a pivotal advancement in modelling MM CAR-T cell activity in this clinically relevant model system. Our approach represents the first time that CAR-T cells were successfully used to treat the Vk12598 model of MM that faithfully recapitulates relapsed MM. The incorporation of lymphodepletion significantly improves CAR-T cell engraftment, in line with clinical CAR-T cell therapy paradigms. The cytokine profile observed is consistent with the cytokine elevations typically observed after CAR-T cell administration in patients. As our construct is capable of binding to both human and mouse BCMA, we are therefore able to fully characterize our lead assets in a relevant model system. Our strategy will enable further research to dissect host-tumour-effector cell interactions, to better inform the design and characterization of novel CAR-T cell therapies in MM.

C-reactive protein impairs immune response of CD8+ T cells via FcγRIIb-p38MAPK-ROS axis in multiple myeloma

BackgroundC-reactive protein (CRP) is a prototypical acute phase protein in humans with the function of regulating immune cells. Serum CRP levels are elevated in multiple myeloma (MM), associated with MM...

Anti-myeloma efficacy of CAR-iNKT is enhanced with a long-acting IL-7, rhIL-7-hyFc

AbstractMultiple myeloma (MM), a malignancy of mature plasma cells, remains incurable. B-cell maturation antigen (BCMA) is the lead protein target for chimeric antigen receptor (CAR) therapy because of its high expression in most MM, with limited expression in other cell types, resulting in favorable on-target, off tumor toxicity. The response rate to autologous BCMA CAR-T therapy is high; however, it is not curative and is associated with risks of cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome. Outcomes in patients treated with BCMA CAR-T cells (CAR-Ts) may improve with allogeneic CAR T-cell therapy, which offer higher cell fitness and reduced time to treatment. However, to prevent the risk of graft-versus-host disease (GVHD), allogenic BCMA CAR-Ts require genetic deletion of the T-cell receptor (TCR), which has potential for unexpected functional or phenotype changes. Invariant natural killer T cells (iNKTs) have an invariant TCR that does not cause GVHD and, as a result, can be used in an allogeneic setting without the need for TCR gene editing. We demonstrate significant anti-myeloma activity of BCMA CAR-iNKTs in a xenograft mouse model of myeloma. We found that a long-acting interleukin-7 (IL-7), rhIL-7-hyFc, significantly prolonged survival and reduced tumor burden in BCMA CAR-iNKT–treated mice in both primary and re-challenge settings. Furthermore, in CRS in vitro assays, CAR-iNKTs induced less IL-6 than CAR-Ts, suggesting a reduced likelihood of CAR-iNKT therapy to induce CRS in patients. These data suggest that BCMA CAR-iNKTs are potentially a safer, effective alternative to BCMA CAR-Ts and that BCMA CAR-iNKT efficacy is further potentiated with rhIL-7-hyFc.

Updated phase I study results of PHE885, a T-Charge manufactured BCMA-directed CAR-T cell therapy, for patients (pts) with r/r multiple myeloma (RRMM).

8004 Background: B cell maturation antigen (BCMA) targeted CAR-T cells are approved for RRMM. Long manufacturing time and high clinical demand limit access. T-Charge, an innovative platform that reduces manufacturing time to <2 days and preserves T cell stemness, results in robust expansion and prolonged CAR T cell persistence. Here we report updated results from the Phase I trial of T-Charge manufactured, fully human, BCMA CAR-T PHE885 (NCT04318327). Methods: Eligible pts had RRMM after ≥2 prior lines of therapy (tx). Pts received fludarabine and cyclophosphamide (or bendamustine) for lymphodepletion (LD) prior to PHE885 infusion. Primary objective was safety. Secondary objectives were clinical response and cellular kinetics. Results: As of December 22, 2022, 46 pts received PHE885 at the following doses: 2.5e6 (n=4), 5e6 (n=13), 10e6 (n=20), 14.3e6 (n=1), and 20e6 (n=8) CAR T cells. PHE885 was manufactured for 61% of pts at a single academic institution; these pts proceeded from apheresis to LD in a median of 16 days. Median age at enrollment was 65 y (range [R] 45-81), median prior lines of tx was 4 (R 2-10). 37% of pts had extramedullary disease; 96% were triple refractory. Despite aggressive disease, only 28% of pts required bridging chemotherapy, predominantly influenced by quick production time. 96% of pts experienced any gr cytokine release syndrome (CRS); 11% had gr 3 CRS. Median time to CRS onset was 8 (R 2-16) days and median duration was 4 (R 1-19) days. Immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 22% of pts; 7% had gr 3 ICANS. Dose limiting toxicities were experienced by 13% of pts and included gr 4 neutropenia, gr 4 lipase increase, gr 3 serum amylase increase, gr 3 neurotoxicity, gr 3 transaminitis, and gr 3 ejection fraction reduction. The most common tx-related gr ≥3 AEs included anemia (54%), neutropenia (50%), and thrombocytopenia (37%). Geo-mean peak PHE885 expansion (Cmax) was 276,000 copies/µg by qPCR and 70.6% of CD3+ T cells by flow cytometry (n=41). The PHE885 transgene was detected in 13/14 (93%) pts at 6 mo and 5/7 (71%) at 12 mo post infusion. T cells with early memory phenotype were preserved in the final product and persisted in pts post infusion. In 43 efficacy-evaluable pts, the ORR was 98%. At 10e6 dose (n=19), ORR was 100% and CRR was 42% (median follow-up of 4.9 mo [R 1.4-11.8]); 60% of 10 evaluable pts were MRD negative at 10-5 by NGS. Initial efficacy data at 20e6 and longer follow-up at active doses will also be presented. Conclusions: T-Charge manufactured PHE885 produced high response rates with no unexpected safety findings in heavily pretreated RRMM pts with aggressive disease. PHE885 expanded rapidly and showed durable persistence in vivo. Since conversion to CR/sCR has occurred as late as 18 months after infusion in this study, longer follow-up is ongoing to identify a recommended dose for future development. Clinical trial information: NCT04318327 .

B- Cell Maturation Antigen (BCMA) Re-Emergence and Relapse Patterns Post-BCMA-Chimeric Antigen Receptor T Cell (CAR-T ) Therapy for Multiple Myeloma

INTRODUCTION: The outcomes of patients (pts) with triple and Penta-class relapsed refractory multiple myeloma (RRMM) are poor. The first B- cell maturation antigen (BCMA) chimeric antigen receptor T cell (CAR-T) therapy in RRMM was FDA approved in March 2021. The overall response rate (ORR) was 73%, with median progression-free survival (PFS) and median overall survival (OS) of 8.8 and 19.4 months, respectively. Undetectable soluble sBCMA levels correlated with the depth of responses, and re-emergence of sBCMA level indicates relapse. Our goal is to evaluate BCMA re-emergence on plasma cells in bone marrow samples using multiparameter flow cytometry (MFC) and correlation with outcome. METHODS: 19 pts who received BCMA CAR-T therapy for RRMM at the University of Kansas Health System between May 2021 and June 2022 were included in the study. Those with less than 3 months of follow-up were excluded from the analysis. Only patients with established negative BCMA on BMBx at day 30 were included. All patients had standard restaging BMBx at 1 mo., 3 mo., 6 mo., and 1 yr. Eight-color MFC was performed on the BMBx specimens. BCMA antibody was purchased from R & D Systems (Minneapolis, MN). Data analysis was performed using FCS Express 5 software (De Novo Software, Los Angeles, CA). 500,000 to up to 2,000,000 events were acquired in all the cases. Responses were evaluated using the International Myeloma Working Group (IMWG) criteria. Kaplan-Meier analyses were used to estimate PFS. Time to BCMA re-emergence was defined as the time from CAR-T cell infusion to positive BCMA on BM PC. RESULTS: Demographic data for 19 RRMM BCMA CAR-T recipients is shown (Table 1). The groups were similar except for higher non-osseous extramedullary disease in the relapsed group. The median follow-up was 9 mo. (3-12 mo.). Nine patients (47.3%) relapsed and ten (52.6%) did not. The median time to relapse was 5 mo. (2 to 12 mo.). BCMA re-emergence was demonstrated in a total of 10 patients (52.6%). Of these, 7 (70%) clinically relapsed and 3 (30%) did not. The median time to BCMA re-emergence was 3 mo. (2-12 mo.). Amongst the nine patients who relapsed, 7 patients (77.7%) demonstrated BCMA re-emergence, of which 5 patients (55.5%) had BCMA re-emergence prior to clinical relapse (Figure1). The median time from BCMA re-emergence to clinical relapse in those 5 patients was 2 mo. (0-7 mo.) Amongst the 10 patients with no relapse, only 3 (30%) demonstrated BCMA re-emergence. CONCLUSIONS: Re-emergence of BCMA after BCMA-directed CAR-T therapy as detected by MFC on BMBx may be a prognostic marker and correlate with responses. Although there was a higher incidence of BCMA re-emergence in the relapsed group, no significant differences were observed due to the small sample size. This warrants further investigation. Prospective studies are needed to evaluate the correlation between BCMA re-emergence with prognosis and prediction of relapse. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Real-World Analysis of Cytopenias after Chimeric Antigen Receptor T-Cell Therapy: A Comparison of BCMA and CD19 Based Outcomes

Introduction: Chimeric Antigen Receptor (CAR) T-cell therapy is now approved as a second-line treatment for relapsed/refractory diffuse large B cell lymphoma (DLBCL), multiple myeloma (MM), and acute lymphoblastic leukemia. B-cell maturation antigen (BCMA) and CD19 CAR-T therapies are associated with substantial hematological toxicity, potentially causing complications in the post-CAR-T setting. It is unclear if cytopenia rates differ between CAR-T therapies. We evaluated differences in cytopenia, transfusion support, and associated outcomes in patients receiving CAR-T therapy for MM and non-Hodgkin's lymphoma (NHL) at our institution. Methods: We performed a retrospective analysis of patients diagnosed with MM and NHL from 2012-2022 who subsequently relapsed and received CAR-T-cell therapy at the Winship Cancer Institute at Emory University. Patients were excluded if they underwent apheresis but had not received infusion or had manufacturing failure. We compared rates of grade 3/4 cytopenias based on CIBMTR criteria and supportive care at day 0, 3mo, 6mo, and 1 year as well as date of hematological recovery. Day 0 was defined as onset of grade 3/4 cytopenia after CAR-T therapy. Hematological recovery was defined as sustained hemoglobin >8g/dL, platelets >50,000/µL, and ANC >1000/mm3 without need for support. Differences between groups were determined using Fisher's exact test and Kruskal-Wallis Test where appropriate. PFS and overall survival (OS) were estimated using the Kaplan-Meier method from CAR-T infusion to progression or death for those events and last contact for those censored. Statistical analysis was performed using SAS with significance at the 0.05 level. Results: Of 35 patients, 24 received BCMA and 11 received CD19 CAR-T therapy. Median age at CAR-T infusion for all patients was 58 years (36-78). Most patients were male (66.7%) and of white race (57.1%) [Table 1]. Overall, 4 patients (11.4%) had an initial ECOG ≥2. Twenty-one patients (87.5%) had penta-refractory MM disease with extramedullary involvement in 25%. All patients with NHL had stage 4 disease with bone marrow involvement in 33.3%. Eight patients had DLBCL (72.7%), 1 double hit lymphoma (18.2%), and 2 mantle cell lymphoma (9.1%). Six patients received tisa-cel, 2 axi-cel, 2 brexu-cel, and 1 liso-cel. The MM cohort underwent significantly more autologous transplantations as a prior line of therapy (p<0.001). Patients with NHL received CAR-T at a later median age (p=0.006). Median follow-up for the MM and NHL cohort was 2.38 years and 0.2 years respectively. There was no difference in time from last therapy to CAR-T infusion (p=0.171) nor days of hospitalization (p=0.681). Almost all patients (95.8%) achieved hematological recovery after infusion with similar recovery rates between groups (p=0.536). Median time to grade 3/4 anemia recovery was 6 days (1-90), neutropenia recovery at 15 days (1-336), and thrombocytopenia recovery at 28 days (14-277). Time to grade 3/4 anemia, neutropenia, and thrombocytopenia was 1 day (0-11), 2 days (0-11) and 2 days (0-15) respectively. Most patients required supportive care with growth factors (34.6%), packed red cells (57.7%), and platelets (23.1%) without significant group differences [Table 2]. One patient with MM received TPO. Prolonged grade 3/4 cytopenia rates were significant with 17.1% at 3mo, 22.9% at 6mo and 8.7% at 1 year. Both groups had similar rates of grade 3/4 cytopenia at day 0, 3mo, 6mo, and 1 year. The MM cohort had higher rates of infection (p<0.001). Rates of CRS (p=0.226) and neurotoxicity (p=0.063) were similar. Fourteen patients with MM (58.3%) and 3 patients with NHL (27.3%) progressed post-CAR-T. Median PFS overall was 1.7 years, 2 years (95%CI: 1, 3) in the MM group, and not reached (NR) (0.2, NA) in the NHL group. Median OS overall was NR, NR in MM (2.5, NA) and NR in NHL (0.3, NA). Grade 3/4 neutropenia and thrombocytopenia were not associated with survival at any time interval. Onset of grade 3/4 cytopenia were not associated with histopathological characteristics, inflammatory markers, or CRS/ICANS. Conclusions: This real-world study demonstrates comparable rates of upfront and prolonged cytopenia in patients receiving BCMA and CD19 CAR-T therapies. Over 20% of patients had prolonged, ongoing grade 3/4 cytopenias requiring supportive care at the 3-6mo mark. Further follow-up and larger prospective studies are needed to validate these findings. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A Systematic Meta-Analysis of Cytokine Release Syndrome Incidence in B-Cell Maturation Antigen-Targeting Chimeric Antigen Receptor T-Cell Therapy and Bispecific Antibodies for Patients with Relapsed and/or Refractory Multiple Myeloma

Introduction: B-cell maturation antigen (BCMA)-targeting immunotherapies (eg, chimeric antigen receptor T cells (CAR-T) and bispecific antibodies (BsAb)) have achieved remarkable clinical responses in patients (pts) with relapsed and/or refractory multiple myeloma (RRMM). Their use is accompanied by exaggerated immune responses related to T cell activation and cytokine elevations leading to cytokine release syndrome (CRS), which could be life-threatening if presenting in high grades. This study utilized a meta-analysis approach to compare CRS profile in BCMA-targeting CAR-Ts vs. BsAbs in pts with RRMM. Methods: CRS profiles for BCMA-targeting CAR-T and BsAb therapies were compiled from publicly available data in published literature up to July 2022. The meta-analysis included 28 CAR-Ts, including 2 approved therapies (idecabtagene vicleucel and ciltacabtagene autoleucel) and 8 investigational BsAb. The weighted proportion of all Grades, Grade 1-2, and Grade ≥3 CRS was estimated using fixed- and random-effects meta-analytic models. Between-study heterogeneity was evaluated using the heterogeneity index (I2) and P-value. Subgroup analyses were performed to assess the differences in CRS incidence and severity across CAR-T and BsAb and routes of BsAb administration (IV vs. SC). Dosing, priming/premedication (premeds) regimens, time to onset, duration of CRS, and CRS management were compared. Results: A total of 53 studies including 2092 RRMM pts treated with BCMA-targeting CAR-T and BsAb therapies were included in the analysis. The meta-analysis showed a significantly higher weighted proportion of CRS with CAR-T therapies vs. BsAb (all Grades 87% (95% CI: 80-93) vs. 67% (95% CI: 58-75), I2= 87%, P-value <0.01; and Grade ≥3 6% (95% CI: 3-9) vs. 0.2% (95% CI: 0.0-1.7), I2= 65%; P-value <0.01 (Figure 1). Average time to CRS onset was delayed (5 days vs. 1 day) and the median duration of CRS was longer (5 days vs. 2 days) after CAR-T compared to BsAb. Use of premeds (eg, corticosteroids, antihistamines, and antipyretics) was reported for 5 BsAb agents, while premeds were not used to reduce CRS severity with CAR-Ts. Tocilizumab and corticosteroids were used to manage CRS in 50% (325/649 pts; 12 studies) and 17% (87/525 pts; 9 studies) of patients, respectively, treated with CAR-T therapies, as compared to 31% (212/677 pts; 13 studies) and 16% (102/625 pts; 9 studies) of patients, respectively, treated with BsAb agents. Two BsAbs evaluated both IV and SC routes (Table 1). A higher incidence of CRS Grade 1-2 was found following SC compared to IV route of BsAb administration: 73% (95% CI: 62-83) vs. 58% (95% CI: 48-68) (I2=73%; P-value= 0.05), respectively. However, higher doses were evaluated with SC compared to IV routes. A higher incidence of CRS Grade ≥3 was observed with BsAb administered IV vs. SC: 0.9% (95% CI: 0.0-4%) vs. 0.0% (95% CI: 0.0-0.3%), respectively (I2= 49%; P-value = 0.05). CRS occurrence by dose number administered was reported for 3 BsAbs. Except for teclistamab, which reported CRS events in 4.8%, 2.4%, 1.2% and 3.6% of pts following the 4th, 5th, 6th, and later doses, respectively, the other 2 BsAbs (CC- 93269 and elranatamab) reported CRS episodes mostly following either the first or second dose, and rarely with the third or later doses. Conclusions: The current analysis showed BCMA CAR-T therapies to be associated with higher CRS incidence, higher rates of Grade ≥3 CRS, longer CRS duration, and more prevalent tocilizumab and steroid use for CRS management compared to BsAb, possibly due to a) higher cytokine production following CAR-T therapies and/or b) use of premedication and priming regimens with BsAb which may improve the CRS profile (Table 1). Despite evaluation of a higher dose range, the proportion of CRS Grades ≥3 was higher with BsAb dosed IV vs. SC suggesting that the SC route of administration may allow exploration of higher doses while reducing the incidence of high-grade CRS. This meta-analysis showed that different types of BCMA-targeting immunotherapies and administration routes could contribute to different CRS profiles. The analysis is limited to published literature, and biases due to missing data or different reporting approaches cannot be excluded (eg, several BsAbs reported CRS rates pooled across doses). The analysis will be updated upon availability of full publications with more granular data. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

MM-198 Anti-BCMA Therapy in Multiple Myeloma: A Single-Center Experience

Triple class exposed/refractory multiple myeloma (MM) represents an unmet medical need because there is no standard of care and overall survival (OS) does not exceed 9 months. B-cell maturation antigen (BCMA) has appeared as an interesting target to treat MM. To indirectly compare the time to access therapy and hospitalization as well as the toxicity and efficacy of BCMA bispecific monoclonal antibodies (BiAbs) and CAR-T. An observational retrospective study was designed including MM patients treated with BCMA CAR-T or BiAbs in clinical trials at the Hospital of Salamanca (October 2018-April 2022). Forty-nine patients were treated with BCMA therapy. N/A. The time to access the treatment and hospitalization, global responses, cytokine release syndrome (CRS), neurotoxicity, infections, progression-free survival (PFS), and OS. Twenty-seven patients (55.1%) received CAR-T and 22 (44.9%) received BiAbs. Thirty-nine (79.6%) patients were triple exposed and 28 (57.1%) were triple refractory. Patients who received BiAbs were treated earlier (12 vs. 56 days; P<0.001) and were hospitalized for less time (13 vs. 21 days; P=0.018). Overall response rate was superior in CAR-T patients (100% vs. 52.4%; P<0.001) as was percentage of CR (70.4% vs. 47.6%; P=0.110). Incidence of CRS was higher in the CAR-T group than the BiAbs group (92.6% vs. 68.2%; P=0.028) as were the percentages of grade 4 neutropenia (92.6% vs. 22.7%; P<0.001) and thrombocytopenia (70.4% vs. 9.1%; P<0.001). Infections were more frequent in the BiAbs group (especially between the first and third month of treatment initiation, 55.6% vs. 14.8%; P=0.004), including COVID-19 infection (50.0% vs. 29.6%; P=0.002). With a median follow-up of 14.3 months (1.1-41.8), PFS was superior in patients treated with CAR-T (18.9 vs. 6.1 months; P=0.045) as was OS (not reached vs. 25.5 months; P=0.016). The times to access therapy and hospitalization were shorter in patients treated with BiAbs. The incidences of CRS and cytopenia were higher in the CAR-T group, but mid-term and COVID-19 infections were more frequent in the BiAbs group. Response, PFS, and OS were superior in patients treated with CAR-T than those treated with BiAbs.

P1446: PHASE I STUDY DATA UPDATE OF PHE885, A FULLY HUMAN BCMA-DIRECTED CAR-T CELL THERAPY MANUFACTURED USING THE T-CHARGETM PLATFORM FOR PATIENTS WITH RELAPSED/REFRACTORY (R/R) MULTIPLE MYELOMA (MM)

Background: Chimeric antigen receptor (CAR)-T cell therapy (tx) is approved for treatment of r/r MM. However, prolonged product manufacturing times and a need for longer duration of response are a major obstacle in this population, necessitating fast manufacture of a reliable and durable CAR-T cell product. Aims: Herein we report updated clinical data from a Phase I trial assessing the fully human B-cell maturation antigen (BCMA) CAR-T cell product PHE885 in adult patients (pts) with r/r MM. Methods: This multicenter, open-label study (NCT04318327) characterizes the safety and efficacy of PHE885 manufactured using the novel T-ChargeTM platform, which takes <2 d to manufacture the final product and relies on in vivo expansion after CAR-T cell infusion. Pts with MM r/r to ≥2 prior lines of tx, including an immunomodulatory drug, proteasome inhibitor, and anti-CD38 monoclonal antibody, were eligible. Pts received fludarabine and cyclophosphamide for lymphodepletion prior to a single PHE885 intravenous injection. Primary objectives were safety, including dose-limiting toxicities (DLTs) and adverse events (AEs). Secondary objectives included clinical response, T-ChargeTM process evaluation, and cellular kinetics. Results: At abstract submission, 22 pts were infused with PHE885 at the following fixed doses: 2.5×106 (n=4), 5×106 (n=12), 10×106 (n=5), and 14.3×106 (n=1) CAR-T cells; 15 pts (4 at 2.5×106, 10 at 5×106, and 1 at 14.3×106) were evaluable for safety and efficacy at the data cutoff for the abstract (October 13, 2021). Longer follow up of these 15 pts and data from additional pts treated at doses of 5×106 and 10×106 will be presented at the annual meeting. Of the 15 pts evaluable at data cutoff, DLTs were reported in 3 pts and included asymptomatic grade (gr) 3 transaminitis (n=1, 14.3×106), asymptomatic gr ≥3 elevated pancreatic enzymes (n=1, 5×106), and gr 4 neutropenia (n=1, 2.5×106). Most frequent tx-related gr ≥3 AEs included neutropenia (n=15, 100%), anemia (n=13, 87%), and thrombocytopenia (n=11, 73%). All pts experienced cytokine release syndrome (CRS) per Lee 2014 criteria; 2 had gr ≥3 CRS (n=1, 5×106; n=1, 14.3×106). Median times to CRS onset and resolution were 7 d (range, 4-12 d) and 11 d (range, 9-22 d), respectively. Tocilizumab (n=13, 87%), steroids (n=11, 73%), anakinra (n=4, 27%), and pressors (n=3, 20%) were used to manage CRS. Gr 2 neurotoxicity occurred in 4 pts (27%). Pts had an overall response rate of 93%, stringent complete response in 33%, very good partial response (VGPR) in 20%, and PR in 40%. Of evaluable pts at 3 mo post infusion, 43% (3/7) had minimal residual disease (MRD) at <10–5 sensitivity[JC(1], while 33% (2/6) were MRD negative at <10–6 by next-generation sequencing. Robust expansion of BCMA CAR-T cells was observed in all pts via qPCR and flow cytometry; maximum expansion (geometric mean Cmax) was 316,000 copies/μg by qPCR and 76% of circulating T cells by flow cytometry. Maximum expansion was reached at a median of 14.2 d by qPCR (13.9 d by flow cytometry). Naive-like T cells present in the leukapheresis were preserved during manufacturing of most PHE885 products as measured by flow cytometry, and an increase in naive/Tscm populations is observed in ≥VGPR pts post-infusion. Summary/Conclusion: Low doses of PHE885 manufactured by T-ChargeTM in <2 d have a manageable safety profile and encouraging clinical activity in pts with r/r MM. PHE885 expands rapidly in vivo, persists for prolonged periods, and demonstrates a relatively naive T-cell phenotype.

Risk factors of tumor lysis syndrome in relapsed/refractory multiple myeloma patients undergoing BCMA CAR-T cell therapy.

To investigate the risk factors of tumor lysis syndrome (TLS) in relapsed/refractory multiple myeloma (MM) patients undergoing B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cell therapy. The clinical data of 99 relapsed/refractory MM patients receiving BCMA CAR-T cell therapy in the First Affiliated Hospital, Zhejiang University School of Medicine from July 2018 to December 2021 were collected in this study. Univariate analysis and multivariate logistic regression were performed to evaluate the risk factors of TLS following BCMA CAR-T cell therapy. Among the 99 patients, TLS occurred in 17 cases (17.2%) with an onset time of (8.9±3.0) d after BCMA CAR-T cell therapy. All TLS patients developed TLS-related clinical manifestations, including 17 cases with renal dysfunction, 8 cases with arrhythmia. All TLS patients developed cytokine release syndrome (CRS) with an onset of 1.0 (1.0, 6.5) d after CAR-T cell therapy, and 13 cases developed grade 3-4 CRS. The levels of serum uric acid, serum creatinine and the ratio of cases with grade 3-4 CRS were significantly higher in TLS patients than in non-TLS patients (all P<0.05). Multivariate logistic regression revealed that serum creatinine ( OR=1.015, P<0.01) and severe CRS ( OR=9.371, P<0.01) were independent risk factors of TLS. Relapsed/refractory MM patients undergoing BCMA CAR-T therapy shows high incidence of TLS, which are related to elevated levels of serum creatinine and severe CRS. TLS can be prevented clinically by reducing serum creatinine and controlling CRS severity.

Risk factors of acute kidney injury during BCMA CAR-T cell therapy in patients with relapsed/refractory multiple myeloma.

To explore the risk factors of acute kidney injury (AKI) during B cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cell therapy in patients with relapsed/refractory multiple myeloma (MM). The clinical data of 99 patients with relapsed/refractory MM who received BCMA CAR-T cell therapy in the First Affiliated Hospital of Zhejiang University School of Medicine from July 2018 to December 2021 was retrospectively analyzed. Dynamic changes of renal function before and after chemotherapy preconditioning and after CAR-T cell infusion were observed. Logistic regression was used to analyze the independent risk factors associated with the occurrence of AKI. Among 99 patients, the AKI occurred in 25 cases with an incidence rate of 25.3%, and the median time was 8.0 (5.5,11.0) d. The AKI grade 1, 2 and 3 accounted for 8.0%, 12.0% and 36.0%, respectively. Logistic regression analysis showed that serum creatinine (SCr) after chemotherapy preconditioning ( OR=1.020, P<0.001), and the grade of cytokine release syndrome (CRS) ( OR=6.501, P<0.01) were independent risk factors for AKI during treatment. The area under the ROC curve (AUC) of SCr after chemotherapy preconditioning in predicting AKI was 0.800 (95% CI: 0.694-0.904, P<0.001); using 83.0 μmol/L as cut-off value, the sensitivity, specificity and Youden index of SCr were 72.0%, 80.8% and 0.528, respectively. The incidence of AKI in patients with grade 3-4 CRS was 39.1%, while that was 13.2% in patients with CRS<grade 3 ( χ 2=8.767, P<0.01). AKI mostly occurred within 15.0 d after CAR-T cell infusion, causing transient severe renal damage. Patients with abnormal renal function after chemotherapy preconditioning should be alert to the occurrence of AKI, and attention should be paid to the management of the CRS.

Clinical features of hemophagocytic syndrome following BCMA CAR-T cell therapy in patients with relapsed/refractory multiple myeloma.

To analyze the clinical features of hemophagocytic syndrome (HLH) following B cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cell therapy in patients with relapsed/refractory multiple myeloma. Ninety-nine patients with relapsed/refractory multiple myeloma (including 3 cases of plasma cell leukemia) undergoing BCMA CAR-T cell therapy (monocentric phaseⅠclinical trial, ChiCTR1800017404) in the First Affiliated Hospital, Zhejiang University School of Medicine from July 2018 to December 2021 were enrolled in the study. The baseline features, laboratory findings, treatment, and clinical response of these patients were analyzed. CAR-T cell associated HLH (carHLH) occurred in 20 patients (20.20%), and the median onset time was 7(0-19) d after cytokine release syndrome (CRS). Patients with carHLH were maily male patients, and manifested as high percentage of abnormal plasma cells, higher incidence of severe CRS (grade 3-4), and robust expansion of CAR-T cells in the peripheral blood (all P<0.05). The levels of interleukin (IL)-6, IL-10 and interferon (IFN)-γ, the peak value of international normalized ratio and D-dimer were elevated, and the valley value of fibrinogen was decreased in patients with carHLH (all P<0.01). All carHLH patients resolved with proper intervention (including 7 cases with tocilizumab, 5 with steroids, 6 with both). The objective response rate in carHLH patients was slightly higher than that in non-carHLH patients [100.0% (17/17) vs. 94.87% (74/78), P>0.05]. The incidence of carHLH is relatively high in BCMA CAR-T cell treated patients, which is closely related to pretreatment tumor cell percentage in bone marrow, expansion of CAR-T cells and the secretion of cytokines. Medication based on tocilizumab and steroids can achieve considerable therapeutic effects in patient with carHLH.

Intention to treat versus modified intention-to-treat analysis in B-cell maturation antigen and CD19 chimeric antigen receptor trials: A systematic review and meta-analysis

IntroductionChimeric antigen receptor T-cell therapy (CART) has revolutionised treatment of haematological malignancies; however, current reporting uses a modified intention-to-treat analysis (mITT) which over-estimates efficacy.We assessed what proportion of CD19 and B-cell maturation antigen (BCMA) CART trials report the number of patients not receiving CART after being enrolled by performing meta-analysis of the mITT and intention-to-treat (iTT) overall response rate (ORR). MethodsPubMed/MEDLINE, EMBASE and Cochrane databases were searched. All prospective clinical trials of CD19 and BCMA-targeting CART enrolling two or greater patients from 1st January 2013 to 1st November 2020 were included. ResultsA total of 28 BCMA CART and 74 CD19 CART trials were identified. These included 10 BCMA CART (35.7%) and 52 (70.2%) CD19 CART trials reporting total number of patients enrolled and number of patients treated with CART. For this cohort of trials, the mITT ORR for BCMA CART was 78.0% (95% confidence interval (CI) = 67.0–89.0%), and the iTT ORR was 70.0% (95% CI = 59.0–80.0%). For CD19 leukaemia CART, the mITT ORR was 87.2% (95% CI = 83.1–91.2), and the iTT ORR was 74.9 (95% CI = 64.8–85.0). For CD19 lymphoma CART, the mITT ORR was 70.7% (95% CI = 63.9–77.5), and the iTT ORR was 58.7% (95% CI = 49.7–67.7). ConclusionAcross BCMA and CD19 CART trials, there is a difference of up to 8–12% in the ORR between modified and iTT analyses and a paucity of information regarding reasons why patients did not receive the intended study treatment.

Safety and Efficacy of Anti-Bcma CAR-T Cells for Relapsed/Refractory Multiple Myeloma: A Systematic Review of Literature

Background: Multiple myeloma (MM) is a plasma cell disorder and demonstrates overexpression of B cell maturation antigen (BCMA). Our objective is to evaluate the safety and efficacy of chimeric antigen receptor T cells (CAR-T) against BCMA in patients with relapsed/refractory multiple myeloma (RRMM). Methods: We conducted a systematic literature search using PubMed, Cochrane, Clinicaltrials.gov, and Embase databases. We also searched for data from society meetings. A total of 935 articles were identified, and 610 were screened for relevance. Results: Data from thirty-one original studies with a total of 871 patients (pts) were included based on defined eligibility criteria, see Table 1. Hu et al. reported an overall response rate (ORR) of 100% in 33 pts treated with BCMA CAR-T cells including 21 complete response (CR), 7 very good partial response (VGPR), 4 partial response (PR). Moreover, 32 pts achieved minimal residual disease (MRD) negative status. Chen et al. reported ORR of 88%, 14% CR, 6% VGPR, and 82% MRD negative status with BCMA CAR-T therapy in 17 RRMM pts. In another clinical trial by Han et al. BCMA CAR-T therapy demonstrated an ORR of 100% among 7 evaluable pts with 43% pts having ≥ CR and 14% VGPR. An ORR of 100% with 64% stringent CR (sCR) and 36% VGPR was reported with novel anti-BCMA CART cells (CT103A). Similarly, Li et al. reported ORR of 87.5%, sCR of 50%, VGPR 12.5%, and PR 25% in 16 pts. BCMA targeting agent, JNJ-4528, showed ORR of 91%, including 4sCR, 2CR, 10MRD, and 7VGPR. CAR-T- bb2121 demonstrated ORR of 85%, sCR 36%, CR 9%, VGPR 57%, and MRD negativity of 100% (among 16 responsive pts). GSK2857916, a BCMA targeting CAR-T cells yielded ORR of 60% in both clinical trials. Three studies utilizing bispecific CART cells targeting both BCMA &amp; CD38 (LCARB38M) reported by Zhao et al., Wang et al., and Fan et al. showed ORR of 88%, 88%, &amp; 100% respectively. Topp et al. reported ORR of 31% along with 5 ≥CR and 5 MRD negative status in 42 pts treated with Bi T-cells Engager BiTE® Ab BCMA targeting antigen (AMG420). One clinical trial presented AUTO2 CART cells therapy against BCMA with an ORR of 43%, VGPR of 14%, and PR of 28%. CT053CAR-BCMA showed 14sCR and 5CR with a collective ORR of 87.5% and MRD negative status of 85% in 24 and 20 evaluable pts, respectively. Likewise, Mikkilineni et al. reported an ORR of 83%, sCR of 16.7%, and VGPR &amp; PR of 25% and 41% in 12 pts treated with FHVH-BCMA T cells. Similar results are also reported in other clinical trials of BCMA targeting CART therapy (Table 1). The most common adverse effects exhibited were grade 1-3 hematologic (cytopenia) and cytokine release syndrome (CRS) (mostly reversible with tocilizumab). Conclusion: Initial data from ongoing clinical trials using BCMA targeting CAR-T therapy have yielded promising results both in terms of improved outcome and tolerable toxicity profiles. Although two phase 3 trails are ongoing, additional data is warranted to further ensure the safety and efficacy of anti-BCMA CAR-T cells therapy in pts with RRMM for future use. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau.